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Meta-Analysis
. 2012 Apr 18;2012(4):CD006243.
doi: 10.1002/14651858.CD006243.pub2.

Trastuzumab containing regimens for early breast cancer

Lorenzo Moja  1 , Ludovica Tagliabue, Sara Balduzzi, Elena Parmelli, Vanna Pistotti, Valentina Guarneri, Roberto D'Amico
Affiliations
Meta-Analysis

Trastuzumab containing regimens for early breast cancer

Lorenzo Moja et al. Cochrane Database Syst Rev. .

Abstract

Background: Approximately one-fifth of women who develop early breast cancer have HER2-positive tumours, which if untreated, have a worse prognosis than HER2-negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on efficacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk.

Objectives: To assess the evidence on the efficacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2-positive early breast cancer.

Search methods: We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010).

Selection criteria: RCTs comparing the efficacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2-positive early breast cancer including women with locally advanced breast cancer.

Data collection and analysis: We collected data from published and unpublished trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration.

Main results: We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease-free survival (DFS) significantly favoured the trastuzumab-containing regimens (HR 0.66; 95% confidence interval (CI) 0.57 to 0.77, P < 0.00001; and HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001, respectively). Trastuzumab significantly increased the risk of congestive heart failure (CHF: RR 5.11; 90% CI 3.00 to 8.72, P < 0.00001); and left ventricular ejection fraction decline (LVEF: RR 1.83; 90% CI 1.36 to 2.47, P = 0.0008). For haematological toxicities, risks did not differ. The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies, but found fewer cardiac toxicities. Studies with concurrent administration gave similar efficacy and toxicity results to sequential studies.

Authors' conclusions: Trastuzumab significantly improves OS and DFS in HER2-positive women with early and locally advanced breast cancer, although it also significantly increases the risk of CHF and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy. Shorter duration of therapy may reduce cardiotoxicity and maintain efficacy, however there is insufficient evidence at present to conclude this due to small numbers of patients in these trials.

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram
2
2
Summary of trials characteristics with focus on concurrent or sequential trastuzumab.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Overall survival: all studies.
5
5
Overall survival stratified by duration of trastuzumab treatment.
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6
Overall survival stratified by concurrent or sequential administration of trastuzumab.
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7
Disease‐free survival: all studies.
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8
Congestive heart failure (CHF): all studies.
1.1
1.1. Analysis
Comparison 1: Effect of trastuzumab, Outcome 1: Overall Survival (OS)‐ all studies
1.2
1.2. Analysis
Comparison 1: Effect of trastuzumab, Outcome 2: OS stratified by duration of trastuzumab administration
1.3
1.3. Analysis
Comparison 1: Effect of trastuzumab, Outcome 3: OS stratified by type of trastuzumab administration
1.4
1.4. Analysis
Comparison 1: Effect of trastuzumab, Outcome 4: Disease Free Survival (DFS) ‐ all studies
1.5
1.5. Analysis
Comparison 1: Effect of trastuzumab, Outcome 5: DFS stratified by duration of trastuzumab administration
1.6
1.6. Analysis
Comparison 1: Effect of trastuzumab, Outcome 6: DFS stratified by type of trastuzumab administration
2.1
2.1. Analysis
Comparison 2: Cardiac toxicity, Outcome 1: Congestive Heart Failure (CHF) ‐ all studies
2.2
2.2. Analysis
Comparison 2: Cardiac toxicity, Outcome 2: CHF stratified by duration of trastuzumab administration
2.3
2.3. Analysis
Comparison 2: Cardiac toxicity, Outcome 3: CHF stratified by type of trastuzumab administration
2.4
2.4. Analysis
Comparison 2: Cardiac toxicity, Outcome 4: Left Ventricular Ejection Fraction (LVEF) decline ‐ all studies
2.5
2.5. Analysis
Comparison 2: Cardiac toxicity, Outcome 5: LVEF decline stratified by duration of trastuzumab administration
2.6
2.6. Analysis
Comparison 2: Cardiac toxicity, Outcome 6: LVEF decline stratified by type of trastuzumab administration
3.1
3.1. Analysis
Comparison 3: Other toxicities, Outcome 1: Neutropenic fever ‐ all studies
3.2
3.2. Analysis
Comparison 3: Other toxicities, Outcome 2: Neutropenic fever stratified by duration of trastuzumab administration
3.3
3.3. Analysis
Comparison 3: Other toxicities, Outcome 3: Anaemia ‐ all studies
3.4
3.4. Analysis
Comparison 3: Other toxicities, Outcome 4: Anaemia stratified by duration of trastuzumab administration
3.5
3.5. Analysis
Comparison 3: Other toxicities, Outcome 5: Neutropenia ‐ all studies
3.6
3.6. Analysis
Comparison 3: Other toxicities, Outcome 6: Neutropenia stratified by duration of trastuzumab administration
4.1
4.1. Analysis
Comparison 4: Brain metastases as site of first relapse, Outcome 1: Brain metastases ‐ all studies
4.2
4.2. Analysis
Comparison 4: Brain metastases as site of first relapse, Outcome 2: Brain metastases stratified by duration of trastuzumab administration
4.3
4.3. Analysis
Comparison 4: Brain metastases as site of first relapse, Outcome 3: Brain metastases stratified by type of trastuzumab administration
5.1
5.1. Analysis
Comparison 5: Sensitivity analysis, Outcome 1: OS ‐ by allocation concealment
5.2
5.2. Analysis
Comparison 5: Sensitivity analysis, Outcome 2: DFS ‐ by allocation concealment
See this image and copyright information in PMC

Update of

References

References to studies included in this review

B31 {published and unpublished data}
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BCIRG006 {unpublished data only}
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HERA {published data only (unpublished sought but not used)}
    1. Dowsett M, Procter M, McCaskill-Stevens W, De Azambuja E, Dafni U, Rueschoff J et al. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA trial. Journal of Clinical Oncology 2009;27:2962-9. - PMC - PubMed
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N9831 {published data only (unpublished sought but not used)}
    1. Combination chemotherapy with or without trastuzumab in treating women with breast cancer. www.clinicaltrials.gov (accessed 1 February 2010).
    1. Halyard MY, Pisansky TM, Dueck AC, Suman V, Pierce L, Solin L et al. Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. Journal of Clinical Oncology 2009;27(16):2638-44. - PMC - PubMed
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NOAH {published data only (unpublished sought but not used)}ISRCTN86043495
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References to studies excluded from this review

Belkacemi 2008 {published data only}
    1. Belkacemi Y, Gligorov J, Ozsahin M, Marsiglia H, De Lafontan B, Laharie-Mineur H et al. Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study. Annals of Oncology 2008;19(6):1110-6. - PubMed
E2198 {published data only}
    1. NCT00003992. Chemotherapy plus monoclonal antibody therapy in treating women with stage II or stage IIIA breast cancer that overexpresses HER2. http://clinicaltrials.gov/ct2/show/NCT00003992 assessed on 15th February 2011.
    1. Sledge GW, O'Neill A, Thor AD, Kahanic SP, Zander PJ, Davidson NE. Pilot trial of paclitaxel-Herceptin adjuvant therapy for early stage breast cancer (E2198). Proceedings of San Antonio Breast Cancer Symposium; 2006 Dec 14-17; San Antonio, Texas, USA. In: Breast Cancer Research and Treatment. Vol. 100 Supplement 1. 2006:106.
GeparQuattro trial {published data only}
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Hurley 2006 {published data only}
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References to studies awaiting assessment

B31‐N9831 2010 {published data only}
    1. Russell SD, Blackwell KL, Lawrence J, Pippen JE Jr, Roe MT, Wood F et al. Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. Journal of Clinical Oncology 2010;28(21):3416-21. - PubMed
HERA 2010 {published data only}
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